1. Technical Field
The invention relates to a process for the continuous production of inhalable medicaments and to an apparatus for carrying out the process.
2. Background Information
Within the framework of the invention, the term “medicament” refers to the active component of a medicament which is commonly also referred to as the psychopharmacological agent or active ingredient.
Inhalatives require a certain form of the medicament. For example, micronised medicaments or active ingredients generally come in solid form. In order to guarantee the inhalability of the medicament, high requirements are placed on the particle size, the particle size distribution, the morphology, the stability and the flow performance.
In general, the entire administered dose of the medicament does not reach the lungs, rather only a part of this does. The particle size has a substantial influence on the proportion of the medicament which actually reaches the lungs. For this reason, particles are preferred which have a diameter of less than 20 μm, preferably less than 5 μm and greater than 0.3 μm. The diameter of the particle should be within the given window and furthermore should have the narrowest possible size distribution. Larger particles are separated off during respiration in the upper airways whilst smaller particles are not deposited in the lungs and these leave again when exhaling.
Within the framework of the present invention, particle diameter means the aerodynamic particle diameter wherein this is defined as the equivalent diameter of a ball of density 1 g/cm3 which has the same sedimentation speed in air as the examined particle.
Furthermore, high requirements are placed on the physical stability of the micronised medicament particles. Particles should preferably exist in stable crystalline form with environmental conditions, to prevent agglomeration by phase transition. The stability of the medicament particles thus has indirect influence on the actual quantity of medicaments which reaches the lungs. For this reason, high requirements are placed on the stability of the medicament in order to guarantee consistent quality, especially a particle size or size distribution of the medicament which is constant over time. This quality feature is indispensable in the field of pharmacy and in the use of medicaments because the effect of the medicament depends on the dose which reaches the lungs and thus, as described above, on the particle size and its size distribution.
The same applies for morphology of the micronised particles since the nature of the particle surface has a direct influence on the inclination of the particle towards agglomeration and thus indirect influence on the particle size itself or the durability of the medicament.
Adjuvants can be added to the micronised medicament, allowing the physico-chemical characteristics of a medicament to be set, wherein these influence the quality-determining parameters such as bio-availability, effectiveness and durability in a desired manner.
Apart from the particle size and the size distribution of the micronised medicament, the type, particle size and quantity ratio of the added adjuvant can decisively influence the medicament dose which reaches the lungs.
Conventional processes for producing inhalable medicaments are generally two-stage, when considered from a roughly-structured viewpoint, wherein in a first stage, the medicament is produced in a solid, generally crystalline form which is transformed into micronised particles in a second stage within the framework of a comminution process. Accordingly to the prior art, milling processes can be used for the comminution process, wherein in particular air-jet milling has attained great significance since it is economical, can be used for a multitude of substances and allows simple separation of the desired particle fractions by means of a downstream cyclone separator.
The disadvantage with the air-jet milling used according to the prior art is that the solid material particles are principally subjected to a considerable force effect during the milling process. This force effect induces considerable local heating and moreover leads to the formation of amorphous portions. As a result of the local heating, air-jet milling or milling as a comminution process in general is not suitable for low-melting, thermally unstable or denaturisable materials.
Furthermore, when storing jet-milled medicaments, agglomeration is often observed since the amorphous portions resulting from the milling process re-crystallise.